Neuro-Oncology
Anti-LGI1 encephalitis
Oct. 03, 2024
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Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
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Leukodystrophies are a heterogeneous group of genetic disorders that affect the white matter of the central nervous system, with some entities also affecting the peripheral nervous system. There are over 30 different leukodystrophies, with an overall population incidence of 1 in 7000 live births (60; 49). They are now most commonly grouped based on the initial pattern of central nervous system white matter abnormalities on neuroimaging. Every leukodystrophy is unique in its clinical presentation and pathologic mechanisms, but there is also significant variability within each leukodystrophy, which poses clinical challenges. However, as our knowledge increases, clinical approaches to patients with leukodystrophies and novel therapeutics are constantly being innovated. In recent years, a number of novel therapeutics have been developed and continue to emerge for many leukodystrophies. Hence, early diagnosis with genetic counseling remains one of the cornerstones of patient care. Newborn screening for some of the leukodystrophies has opened new horizons for the disease and increased the need for neurologists to understand and be aware of the need of preventive care for presymptomatic patients.
• Leukodystrophies are defined as genetic disorders that primarily affect the white matter predominantly of the central nervous system; these disorders have either glial cell or myelin sheath abnormalities. | |
• There are other entities called genetic leukoencephalopathies that also are characterized predominantly with white matter abnormalities but do not meet the criteria for being defined as a leukodystrophy. | |
• The pattern of abnormalities on brain MRI is one of the most useful diagnostic tools. | |
• Newborn screening and emerging novel therapies such as gene therapy and small molecule therapies affecting change to the CNS are changing the landscape for many leukodystrophies, making it important for neurologist to be aware of many of these disorders. |
The first leukodystrophy was identified in the early 20th century. Both Nissl and Alzheimer coincidentally reported metachromatic staining of the white matter of an adult patient diagnosed with what we now call metachromatic leukodystrophy (05; 42). Globoid cell leukodystrophy, or Krabbe disease, was described in 1916 when Hallervorden suggested that globoid cells may contain kerasin or cerebroside. Biochemical and histochemical studies confirmed the presence of cerebroside in globoid cells (06), and galactocerebroside was the only glycolipid that could produce globoid cells when experimentally injected into the central nervous system of animals. Until the early 1990s, the known leukodystrophies were metachromatic leukodystrophy, Krabbe disease, Canavan disease, Alexander disease, adrenoleukodystrophy, Pelizaeus-Merzbacher disease, and two forms of adult-onset autosomal dominant leukodystrophies (03).
One difficulty has been in differentiating which clinical syndrome qualifies as a leukodystrophy rather than a leukoencephalopathy. Over the years, multiple terminologies, including demyelination, dysmyelination, leukoencephalopathy, and leukodystrophy, have been used for the varied spectrum of clinical and radiological phenotypes with white matter involvement. Most recently, a consensus of experts in the field better defined the terms. Leukodystrophies are defined as “heritable disorders affecting the white matter of the central nervous system with or without peripheral nervous system involvement with common glial cell or myelin sheath abnormalities.” Disorders with significant white matter abnormality that does not meet the inclusion criteria for leukodystrophies are considered genetic leukoencephalopathies (60).
The consensus definition does emphasize that CNS diseases in which neuropathology shows primary involvement of neurons in the cerebral cortex or other gray matter structures, but in which brain MRI also detects significant abnormalities of white matter, should not be characterized as leukodystrophies. For example, disorders like San Filippo disease, Batten disease, etc., which can cause secondary white matter abnormalities, are not defined as leukodystrophies. Similarly, disorders that are primary vasculopathies resulting in white matter abnormalities are also not classified as leukodystrophies (eg, COL4A2-, COL4A1-, and CADASIL-related disorders). Interestingly, the definition does not discriminate based on clinical presentation. Many of the leukodystrophies do not present as such (eg, adrenomyeloneuropathy, PLP1 presenting as spastic paraplegia). Also, the clinical progression does not need to be progressive to meet the definition of leukodystrophy; for example, megalencephalic leukoencephalopathy with subcortical cysts caused by HEPACAM mutations can be characterized by clinical improvements. The disease presentations can also present with a wide spectrum for age of onset with a broader spectrum of disease being recognized, with growing access to genetic testing.
Name of disorder |
Mode of inheritance |
Biochemical testing |
Molecular genetics |
18q minus syndrome |
Most often de novo deletion; may be inherited | ||
Adult-onset leukodystrophy with neuroaxonal spheroids and pigmented glia (including hereditary diffuse leukoencephalopathy with spheroids and pigmentary type of orthochromatic leukodystrophy with pigmented glia) |
AD |
CSF1R | |
Aicardi-Goutières syndrome |
Usually AR; may be AD |
In CSF: lymphocytosis, increased INF-alpha, increased pterins In plasma: increased liver enzymes, thrombocytopenia |
TREX 1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11, RNU7-1 |
Alexander disease |
AD |
GFAP | |
Autosomal dominant leukodystrophy with autonomic disease |
AD |
LMNB1 | |
Canavan disease |
AR |
In urine and CSF: increased N-acetylaspartic acid |
ASPA |
Cerebrotendinous xanthomatosis |
AR |
In plasma: increased cholestanol, normal to low cholesterol, increased lactate In bile, urine, and plasma: increased bile alcohols and glyconjugates In CSF: increased cholestanol and apolipoprotein B |
CYP27A1 |
Chloride ion channel 2-related leukoencephalopathy with intramyelinic edema |
AR |
CLCN2 | |
eIFB2 -related disorder (vanishing white matter disease or childhood ataxia with central nervous system hypomyelination) |
AR |
In CSF: increased glycine |
EIF2B1-5 |
Fucosidosis |
AR |
On urinary oligosaccharide assay: increased fucose-containing glyconjugates In leukocytes and fibroblasts: decreased alpha-fucosidase activity |
FUCA1 |
Globoid cell leukodystrophy (Krabbe disease) |
AR |
In leukocytes: decreased galactocerebrosidase activity Plasma: increased psychosine |
GALC |
Hypomyelination with atrophy of the basal ganglia and cerebellum |
AD |
TUBB4A | |
Hypomyelination with brainstem and spinal cord involvement and leg spasticity |
AR |
DARS1 | |
Hypomyelination with congenital cataract |
AR |
FAM126A | |
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation |
AR |
DARS2 | |
Leukoencephalopathy with thalamus and brainstem involvement and high lactate |
AR |
EARS2 | |
Megalencephalic leukoencephalopathy with subcortical cysts |
AR (MLC1 and MLC2A) |
MLCI, MLC2A, MLC2B | |
Metachromatic leukodystrophy |
AR |
In leukocytes and fibroblasts: decreased arylsulfatase activity In urine: increased sulfatides |
ARSA |
Oculodentodigital dysplasia |
Usually AD, may be AR |
GJA1 | |
Pelizaeus Merzbacher disease |
X-linked |
PLP1 | |
Pelizaeus Merzbacher like-disease |
AR |
GJC2 | |
Peroxisomal biogenesis disorders (including Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease) |
AR |
Plasma VLCFA, phytanic and pristanic acid; plasma and urine pipecolic acid and bile acids help distinguish different forms of peroxisomal disorders |
PEX genes |
Pol III-related disorders (4H syndrome: hypomyelination, hypodontia, hypogonadotropic hypogonadism) |
AR |
POLR3A, POLR3B | |
Polyglucosan body disease |
AR |
In leukocytes: decreased 1,4 alpha glucan branching enzyme 1 activity Histopathologic examination of muscles, nerve, axillary skin: pathologic polyglucosan accumulation |
GBE1 |
RNAse T2 deficient leukoencephalopathy |
AR |
RNASET2 | |
Sialic acid storage disorders (Salla disease, infantile sialic acid storage disease, and intermediate form) |
AR |
In urine and fibroblasts: increased free sialic acid |
SLC17A5 |
Single enzyme deficiencies of peroxisomal fatty acid beta oxidation (including only D-bifunctional protein deficiency; sterol carrier protein deficiency; peroxisomal acyl-CoA-oxidase deficiency) |
AR |
Plasma VLCFA, phytanic and pristanic acid; plasma and urine pipecolic acid and bile acids help distinguish different forms of peroxisomal disorders |
DBP deficiency: HSD17B4 SCPx deficiency: SCP2 Acyl-Coa-oxidase deficiency: ACOX1 |
Sjögren-Larsson syndrome |
AR |
In urine: abnormal metabolites of leukotriene B4 In fibroblasts and leukocytes: decreased fatty aldehyde dehydrogenase activity or of fatty alcohol: NAD reductase activity |
ALDH3A2 |
SOX10-associated PCWH (peripheral demyelinating neuropathy, central demyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease) |
AD |
SOX10 | |
X-linked adrenoleukodystrophy |
X-linked |
On plasma VLCFA assay: increased C26:0, ratio of C24:0 to C22:0, ratio of C26:0 to C22:0 |
ABCD1 |
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Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125